|HEAD||Dr. LONGACRE Shirley / firstname.lastname@example.org|
|MEMBERS||Dr. FALANGA Pierre / Dr. DELRIEU Isabelle / ROSARIO Sandrine (MAGNAN Mélanie, remplaçante)/ JOOS Charlotte (doctorante)
LVP activities focus on the two major components of subunit vaccines: recombinant protein antigens and novel approaches to immuno-stimulation. Initial efforts concentrated on antigens for malaria vaccine(s), and more recently on others specific for another infectious disease, but the approaches developed may be broadly applicable to vaccines targeting other pathogens.
Recombinant subunit vaccine antigens
Target antigens are produced in the baculovirus/insect cell expression system, which reliably reproduces proteins with complex native conformations, as well as eukaryotic post-translational modifications. Past work has focused on C-terminal merozoite surface protein 1 (MSP1p19), a leading vaccine candidate for both P. falciparum and P. vivax malaria. A large series of positive results in many primate challenge trials using these antigens, led to the production of a clinical lot of PfMSP1p19 in 2007, with a 2nd batch planned in Q2-2008 for technical reasons, in view of a phase-1 clinical trial. The LVP has been heavily involved in the technical issues associated with GMP production. The figure shows superimposed X-ray crystallographic structures of PfMSP1p19 and PcMSP1p19 closely related to P. vivax, both determined with baculovirus recombinant proteins (collaboration G. Bentley, IP). Other baculovirus recombinant MSP antigens (PfMSP4 and PfMSP5) are promising vaccine candidates, and human antibodies to PfMSP1p19 and PfMSP4 in particular have been shown to be major mediators of neutrophil respiratory burst activity, which is highly correlated with acquired long-term clinical protection from malaria (submitted to PLoS Medicine). Patent applications have been filed by the IP for all of the malaria antigens.
Good imuno-stimmulators are needed to boost immune responses to the highly purified recombinant antigens required under increasingly stringent regulatory guidelines, which are generally poorly antigenic when administered alone. The LVP has been investigating a novel approach to augment the immunogenicity of subunit vaccine antigens. We have shown that the baculovirus expression system can carry out a post-translational modification on recombinant MSP1p19, which apparently mediates dramatically enhanced immunogenicity in mice, especially for IgG isotypes associated with cellular immune mechanisms. Our current main objective is to confirm the initial proof-of-principle observations using other antigens targeting malaria and another infectious disease of current interest, for which there is a murine challenge model available to us. We plan also to verify that the modified antigens are not toxic in primates. Concurrently we are actively exploring different expression systems and purification protocols to optimize the expression of the modified antigens, under conditions appropriate for subsequent scale-up.
Keywords: Subunit vaccines, bacculovirus, malaria immuno-stimulation
Polson H, Conway D, Fandeur T, Mercereau-Puijalon O, Longacre S (2005) Gene polymorphism of Plasmodium falciparum merozoite surface proteins 4 and 5, Mol. Biol. Parasit. 142, 110-115.
Bonnet S, Pêtres S, Holm I, Fontaine T, Rosario S, Roth C, and Longacre S (2006) Soluble and glyco-lipid modified baculovirus Plasmodium falciparum C-terminal Merozoite Surface Protein 1, two forms of a leading malaria vaccine candidate. Vaccine 24, 5997-6008.
Perraut R, Marrama L, Diouf B, Sokna C, Tall A, Nabeth P, Trape J-F, Longacre S, & Mercereau-Puijalon O (2005) Antibodies to the conserved C-terminal domain of the Plasmodium falciparum merozoite surface protein-1 and to the merozoite extract and their relationship with in vitro inhibitory antibodies and protection against clinical malaria in a Senegalese village. J. Infect. Dis. 191, 264-271.
S. Longacre, H. Polson, R. Perraut, F. Nato (patent appl) Recombinant Plasmodium falciparum merozoite surface proteins 4 and 5 and their use [of polypeptides and specific antibodies for vaccines, diagnostic methods, kits and anti-parasite therapy.] U.S.A. Patent Application N° 11/603,310 and Confirmation N° 1123, filed 23 November 2005; PCT International Application filed 22 November 2006.
Activity Reports 2007 - Institut Pasteur
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